Circadian Regulation of Antibiotic Resistance in the Microbiome

项目摘要 人类必须调节与近100万亿肠道细菌的共生关系，这些细菌很容易庇护 抗生素耐药基因及其传播机制。尽管抗生素的使用量持续上升 耐药感染对体内调节抗生素耐药性发展的宿主因素知之甚少。 初步调查显示，哺乳动物的生物钟可能是这样一个因素。先前的体内研究 已经证明生物钟驱动微生物群组成的日常节律，这是 与昼夜周期同步。然而，微生物组在昼夜节律时间尺度上的基因表达是 很大程度上是未被开发的。为此，对小鼠的微生物群进行了全面的研究 昼夜光循环。这些数据表明，除了微生物数量的日常节律之外，广泛的 在整个昼夜光循环中，微生物体内存在转录节律。事实上，抗生素耐药性 水平基因转移系统显示了一些最显著的转录节律 微生物组，在每天4小时的窗口内达到表达高峰。这些初步数据表明 微生物体内的转录在时间上是有结构的。这些日(日)节律是 由宿主的生物钟调节的。因此，这项提议试图理解 通过检测细菌在体内的调节，研究微生物组中驱动细菌昼夜转录的机制 水平基因转移和宿主生物钟对抗生素耐药性传播的影响。已被占用 总而言之，这项工作提出了生物钟将微生物组中的转录与昼夜同步 循环，潜在地揭示了哺乳动物对抗生素耐药性发展的调节。

Project Summary Humans must regulate a symbiotic relationship with almost 100 trillion intestinal bacteria which readily harbor antibiotic resistance genes and the mechanisms that spread them. Despite the relentless rise of antibiotic resistant infections little is known about the host factors that regulate antibiotic resistance development in vivo. Preliminary investigations revealed that the mammalian circadian clock may be such a factor. Prior in vivo studies have demonstrated that the circadian clock drives daily rhythms in microbiome composition which are synchronized to the day-night cycle. However, gene expression in the microbiome at circadian time scales is largely unexplored. To this end, a comprehensive study of the mouse microbiome was performed across the day-night light cycle. These data revealed that beyond daily rhythms of microbe abundances, extensive transcriptional rhythms occur in the microbiome across the day-night light cycle. Indeed, antibiotic resistance and horizontal gene transfer systems showed some of the most significant transcriptional rhythms in the microbiome, reaching peak expression within a 4-hour window each day. These preliminary data demonstrated that transcription in the microbiome is temporally structured in vivo. These diurnal (daily) rhythms are characteristic of regulation by the host’s circadian clock. Therefore, this proposal seeks to understand mechanisms driving diurnal bacterial transcription in the microbiome by examining the in vivo regulation of horizontal gene transfer and the impact of the host circadian clock on the spread of antibiotic resistance. Taken together, this work proposes the circadian clock synchronizes transcription in the microbiome to the day-night cycle, potentially revealing a mammalian regulator of antibiotic resistance development.